The endocannabinoid system

A biological system responsible for maintaining homeostasis

The Endocannabinoid system

The endocannabinoid system is present throughout the body and involved in the homeostatic control of many physiological systems; including energy metabolism, cardiovascular and reproductive functions, inflammation, glaucoma, cancer, liver and musculoskeletal disorders, appetite, learning and memory, anxiety, depression, schizophrenia, stroke, multiple sclerosis, neurodegeneration, addiction, and epilepsy.1

Figure adapted from Maccarrone M, et al. 20152 and Zou S, et al. 2018.1

Endocannabinoids

Endocannabinoids are the endogenous mediators that interact with the molecular targets of the endocannabinoid system to regulate homeostasis. The two best-known endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG).

Cannabinoid receptors

The endocannabinoid system formally consists of two main receptors, cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors.

CB1 and CB2 receptors are both seven-transmembrane G protein-coupled receptors. CB1 receptors are most highly expressed in the brain but also are present in adipose tissue, and peripheral organs at varying levels.3 Within the central nervous system, CB1 receptors are the most abundant G protein-coupled receptor, with highest expression in the basal ganglia, hippocampus, cortex and cerebellum.4

CB2 receptors, on the other hand, are mainly expressed peripherally in organs associated with the immune system.3 The expression of CB2 receptors in the central nervous system remains controversial with conflicting evidence regarding its low expression on neurons and/or microglia.5,6

Additional to the cannabinoid receptors there are several other receptors, including G protein-coupled receptors (e.g. GPR55), ion channel (transient receptor potential channels) and nuclear receptors (peroxisome proliferator-activated receptors), that also interact with cannabinoids and thus might be considered part of the broader endocannabinoid system.

How endocannabinoid signaling puts the “brakes” on neural transmission

Endocannabinoids work “on-demand” in a “retrograde” manner to regulate homeostasis. In the brain, they halt or “put the brakes” on neural signaling.
Within neurons, endocannabinoids are synthesized “on-demand”, i.e. in response to neuronal activation in the post-synaptic neuron. They travel in a retrograde manner, backwards across the synapse to the presynaptic neuron, where CB1 receptors are located. Endocannabinoids bind and activate CB1 receptors, which are predominantly coupled to intracellular machinery that cause inhibition of neurotransmitter release. By inhibiting the release of further neurotransmitters, further neuronal activation is limited.

References

  1. Maccarrone M, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015; 36(5): 277-296.
  2. Zou S, et al. Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. Int J Mol Sci. 2018; 19(833).
  3. Fagerberg L, et al. 2014, ‘Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics’. Mol Cell Proteomics. 2014; 13(2): 397-406.
  4. Chen D, et al. ‘Brain cannabinoid receptor 2: expression, function and modulation’. Acta pharmacologica Sinica. 2017; 38 (3): 312-316.
  5. Howlett A and Abood M. ‘CB1 and CB2 Receptor Pharmacology’. Adv Pharmacol. 2017; 80: 169-206.
  6. Li Y and Kim J. ‘Distinct roles of neuronal and microglial CB2 cannabinoid receptors in the mouse hippocampus’. Neuroscience. 2017; 363: 11-25.